(3dg) Fundamentals of Physically Crosslinked Biomaterials for Improved Design and Development of Healthcare Solutions

Biomaterial based physically crosslinked hydrogels (PHs) have enabled novel strategies in the development of injectable drug delivery materials, 3D bioprinting, and tissue regeneration applications. They paradoxically offer both solid and liquid like properties, allowing for simple extrusion with subsequent, rapid gelation without the need for secondary reaction strategies or input stimuli. In prolonged drug delivery, PHs are promising material platforms for prolonging drug release over months long durations, enabling transformative treatments for chronic diseases such as diabetes. However, prolonging release can preclude injectability, eliminating the applicability of PHs in a clinical setting. Similarly, in 3D printing there is a challenge in creating extrudable materials that solidify fast enough to maintain a three dimensional structure. In both of these applications, PHs must satisfy design constraints for both the end function (i.e. prolonged drug release) and the administration/delivery process (i.e. injection). Engineering PHs with the viscoelastic, flow, and yielding behavior capable of satisfying these constraints is extremely challenging. To date, most advances have relied on trial and error approaches, which are slow and expensive. There is a strong need for new model-based design strategies for PHs that improve our approach for engineering PHs to satisfy the multiple constraints imposed by drug delivery and bioprinting applications.

My future research will explore fundamental structure-property-function relationships for biomaterial PHs to create new design paradigms for engineering the next generation of advanced healthcare technologies.

Overall, my future work will focus on identifying and characterizing the effects of composition, including interaction dynamics, concentrations, and topology on the rheological and diffusive materials properties of biomaterial PHs. For this purpose, I will employ my interdisciplinary background in rheology, polymer physics, and chemistry to integrate the synthesis of new materials with rigorous mechanical and diffusive characterization. My work will establish the relationship between PH’s intrinsic material properties and overall function. These new materials will enable improved drug delivery strategies with selective, and independent control over in situ and process function, allowing for prolonged drug delivery without precluding injectability. Furthermore, the property-function relationships discovered in my work will accelerate the materials discovery process for both my research and others by identifying and establishing the necessary properties for effective injectable drug delivery and bioprinting systems.

Research Experience:

Designing Polymer-nanoparticle hydrogels for Drug Delivery

Department of Materials Science and Engineering, Stanford University (advised by Eric Appel)

My postdoctoral research has focused on investigating the rheological behavior of physically crosslinked hydrogels and on designing them as material solutions for complex challenges. Specifically I investigated polymer-nanoparticle hydrogels (PNPs), crosslinked by dynamic hydrophobic interactions, and their broad applicability in adhesion prevention after myocardial infarction, wildfire prevention, drug-delivery, and cell transplantation. While these applications are seemingly disparate, careful analysis reveals that they have similar design criteria, benefiting from a material capable of dynamic rearrangement (flow) followed by localization and permanence. As yield stress fluids, PNPs are capable of a solid to liquid (yielding) transition when sheared followed by a rapid recovery to a solid and were demonstrated to satisfy the design requirements of each application. I investigated (1) how processes can impose constraints on potential materials solutions and (2) how the hydrophobic modifications affect shear-thinning and dynamic network formation for PNPs. For example, we found that injectable drug delivery strategies impose design constraints on the viscosity, shear thinning, network formation kinetics, and diffusion of the material being injected. Adhesion prevention imposes constraints on the yield stress and sprayability of the material being used. A non-monotonic relationship between clinical efficacy and yield stress was observed.

Development and Characterization of Poly(phthalaldehyde) for Transient Applications Department of Mechanical Science and Engineering (advised by Scott R. White)

My thesis research developed a novel autonomous material platform capable of disintegrating on-demand, enabling the invention of solid state transient (destructible) polymer films and devices. Metastable polymers that depolymerize in response to environmental stimuli to change shape, form, or function have garnered increased research interest with applications in signal amplification, temporary electronics, recycling, and drug delivery. These transient applications take advantage of the large transformation in properties that accompany the depolymerization of high molecular weight polymers into their monomeric components. My PhD research consisted of a detailed investigation of the metastable polymer cyclic polyphthalaldehyde (cPPA). Depolymerization of cPPA was controlled by incorporating light and thermal responsive agents that destabilize the cPPA upon exposure to the corresponding stimuli. cPPA was triggered to depolymerize into its monomeric component by exposure to heat or acid. Its degradation in response to these stimuli was chemically characterized with fourier transform infrared spectroscopy, confocal Raman spectroscopy, and NMR. The effects of degradation on the mechanical performance was explored using dynamic mechanical analysis. With precise control over the triggered depolymerization of cPPA, transient electronic devices were created that could be destroyed on-demand. Thermal triggering was shown to volatilize the transient substrates, leaving only 15% of its mass as residue after thermal triggering. Furthermore, we investigated a long standing challenge for the synthesis and stabilization of cPPA by investigating the effects of initiator concentration on film stability, resulting in a repeatable and reliable synthesis of cPPA that could be thermoformed to create bulk three dimensional cPPA plastic components.

Selected Publications:

• L. M. Stapleton, A. N. Steele, H. Wang, H. Lopez Hernandez et al. “An Effective Post-Operative Pericardial Adhesion Barrier Utilizing Polymer-Nanoparticle Hydrogels”. Nature BME. 2019 In Press.
• E. M. Lloyd, H. Lopez Hernandez, A. M. Feinberg, M. Yourdkhani, E. K. Zen, E. B. Mejia, N. R. Sottos, J. S. Moore, S. R. White. “Fully Recyclable Metastable Polymers and Composites”. Chem. Mater. 2019, 31, 398.
• H. Lopez Hernandez, S. K. Takekuma, E. B. Mejia, C. L. Plantz, N. R. Sottos, J. S. Moore, S. R. White. “Processing-dependent mechanical properties of solvent cast cyclic polyphthalaldehyde.” Polymer. 2019, 162, 29.
• H. Lopez Hernandez, A. K. Grosskopf, L. M. Stapleton, G. Agmon, E. A. Appel. “Non-Newtonian Polymer-Nanoparticle Hydrogels Enhance Cell Viability during Injection”. Macromol. Biosci. 2019, 19, 1800275.
• H. Lopez Hernandez, O. P. Lee, C. M. Possanza Casey, J. A. Kaitz, C. W. Park, C. L. Plantz, J. S. Moore, S. R. White. “Accelerated Thermal Depolymerization of Cyclic Polyphthalaldehyde with a Polymeric Thermoacid Generator”. Macromol. Rapid Commun. 2018, 39, 1800046.
• H. Lopez Hernandez*, A. M. Feinberg*, C. L. Plantz, E. B. Mejia, N. R. Sottos, S. R. White, J. S. Moore. “Cyclic Poly(phthalaldehyde): Thermoforming a Bulk Transient Material”. ACS Macro Lett. 2018, 7, 47.
• O. P. Lee, H. Lopez Hernandez, J. S. Moore. “Tunable Thermal Degradation of Poly(vinyl butyl carbonate sulfone)s via Side-Chain Branching”. ACS Macro Lett. 2015, 4, 665.
• C. W. Park, S.-K. Kang, H. Lopez Hernandez, J. A. Kaitz, D. S. Wie, J. Shin, O. P. Lee, N. R. Sottos, J. S. Moore, J. A. Rogers, S. R. White. “Thermally Triggered Degradation of Transient Electronic Devices”. Adv. Mater. 2015, 27, 3783.
• H. Lopez Hernandez, S.-K. Kang, O. P. Lee, S.-W. Hwang, J. A. Kaitz, B. Inci, C. W. Park, S. Chung, N. R. Sottos, J. S. Moore, J. A. Rogers, S. R. White. “Triggered Transience of Metastable Poly(phthalaldehyde) for Transient Electronics”. Adv. Mater. 2014, 26, 7637.

* Equal Contributions

Selected Awards:

2018 Stanford Polymer Collective Art of Science Award

2017 -- 2018 NSF AGEP Postdoctoral Fellowship (California Alliance)

2016 -2017 Mavis Future Faculty Fellowship

2016 Mechanical Science and Engineering Teaching Fellow

2016 1st Place Poster at SACNAS Conference

2015 -2016 Beckman Institute Graduate Research Fellowship

2015 1st Place Graduate Student Presentation Award at SACNAS Conference \\

2015 Academic Excellence and Good Citizenship Award, University of Illinois Graduate College

Teaching Interests:

I am excited about the opportunity to teach and mentor up and coming classes of engineers. I have been active in my mentorship training, mentoring several undergraduates during my graduate and postdoctoral research positions. I have also pursued formalized teaching training at the University of Illinois and Stanford University, where I am pursuing the teaching certificate. As mechanical engineer, I am excited and qualified to teach heat transfer, thermodynamics, mathematics and fluid mechanics. I am also willing and capable of teaching other core curriculum courses. I am looking forward to developing and teaching courses in polymer physics, rheology, and polymer science and engineering (solid state). In the laboratory, I am looking forward to mentoring my postdoctoral researchers, graduate student researchers, and also any undergraduates that are searching for research experience. I will help prepare them for their career path, providing them with the resources and guidance needed to achieve their goals. My laboratory will take a multidisciplinary approach, using principles from engineering, chemistry, biology, physics, and materials science to tackle our research questions.

Teaching Experience:

• Stanford Teaching Certificate, in progress
• Guest Lecturer, Organic and Biological Materials, Entropic Elasticity and Rheology Lectures. MATSCI 210. Department of Materials Science and Engineering, Stanford University, Spring 2018 - 2020
• Teaching and Leadership Course, ENG 598. University of Illinois at Urbana-Champaign, Spring 2017.
• Teaching Fellow Lecturer, Experimental Stress Analysis, Lecture and Laboratory Course, TAM 456. Department of Mechanical Science and Engineering, University of Illinois at Urbana-Champaign, Spring 2016.